Gut-Liver-Brain Axis and Alcohol Use Disorder: Treatment Potential of Fecal Microbiota Transplantation

As hepatology providers, we assemble a toolbox of interventions to treat acute and chronic liver diseases with a goal to prevent fibrosis progression, HCC, and hepatic decompensation while also improving the quality of life and survival of our patients (Figure 1). This toolbox has been built based on our experiences during clinical training and the practice of routine patient care. We are comfortable with a diverse set of tools, from antivirals to immunosuppressive medications, vasoactive medications to beta-blockers, as well as performing interventions such as endoscopy, banding, paracentesis, and liver biopsies. Hepatology providers have accepted that in the setting of chronic liver disease, we are primarily responsible for prescribing interventions, which treat the underlying liver insult and follow-up on outcomes and side effects using a multidisciplinary approach. Yet, when it comes to the management of alcohol use disorder (AUD) in the setting of alcohol-associated liver disease (ALD), our discipline seems to have made an exception. Although treatment of AUD has been identified as a quality metric in the care of patients with liver disease,1 rates of AUD treatment in those with ALD are astonishingly low,2,3 and current societal recommendations are to refer elsewhere for AUD management once identified.4,5 Why has this culture evolved among hepatology providers? Is it a lack of knowledge and/or comfort in AUD treatment? Do patients with AUD and their providers have difficulty accessing the tools when needed? Importantly, can social stigma and sociocultural considerations influence patient participation in AUD treatment? The answer is all of the above.FIGURE 1: The hepatology toolbox—how do we include alcohol use disorder treatment?.DESPITE THE BENEFIT, TREATMENT OF AUD IN ALD RARELY HAPPENS It is universally agreed that alcohol abstinence is the cornerstone of ALD management, as it is associated with improved liver-related outcomes3 and is cost-effective and even cost-saving in those with ALD cirrhosis.6 Yet despite this, 2 large cohort studies of individuals with AUD and ALD cirrhosis have shown that only ~15% receive AUD behavioral therapy and a mere 1% receive pharmacotherapy.2,3 Why are AUD treatment rates so low? To begin, data have suggested that apart from psychiatry and addiction medicine, physicians receive minimal training in AUD identification and management and do not feel equipped to treat it. Surveys by GI/hepatology providers suggest that almost all screen universally for frequency and quality of alcohol consumption; however, almost half never/rarely screen for AUD, and 70% never/rarely prescribe AUD therapy.7 The most common provider-perceived barriers to prescribing AUD pharmacotherapy were lack of training, unfamiliarity, and lack of time. Other studies have identified patient-perceived barriers, including lack of apparent benefit to treatment, financial and insurance obstacles, and access to transportation.8 However, in addition to these hurdles, other patient-related barriers are faced disproportionately by those most vulnerable in society. SOCIOCULTURAL AND EQUITY CONSIDERATIONS INFLUENCING DELIVERY OF AUD/ALD THERAPY A significant proportion of individuals with AUD/ALD are from historically underrepresented racial/ethnic, sex/gender, and sociocultural groups9 and those vulnerable in their social determinants of health, creating additional barriers to AUD treatment (Figure 2). These disparities are complex and historically rooted in patterns of systemic discrimination and socioeconomic disadvantage.10 Overall, AUD treatment is most effective as a combination of pharmacologic and behavioral interventions, yet most studies evaluating AUD treatment underrepresent those of diverse cultural, racial/ethnic, and sex/gender backgrounds and have not been designed to address important dimensions of diversity. In considering those vulnerable in social determinants of health, pharmacologic treatments require public and/or private insurance to cover costs, while in addition to cost, behavioral therapy also requires significant time and social resources to participate. These include the ability to take time from work in those employed and/or the ability to delay home obligations if caring for dependents. Individuals must also secure transportation and be in proximity to AUD behavioral treatment, or if able to be delivered remotely, have access to technological resources for participation. Finally, culturally and linguistically appropriate AUD services are required to provide safe and equitable access to AUD treatment to all but are not universally accessible. Moving forward, these important aspects of diversity will need to be considered in the development and delivery of AUD services.FIGURE 2: Barriers to alcohol use disorder treatment in vulnerable populations.SPECIAL CONSIDERATIONS FOR WOMEN AND YOUTHS Women and youths have been identified as populations experiencing a disproportionate increase in harm from AUD/ALD and have emerged as priority groups in need of AUD treatment.11,12 Women and youths with AUD have a high prevalence of co-morbid mental health conditions and have experienced mental, physical, and/or sexual abuse, which can impact participation and outcomes of treatment. Although outcomes of AUD treatment are comparable between sexes, women are less likely to receive treatment than men.12 Unique factors among women that can influence participation in AUD treatment include issues surrounding motherhood, such as the need for childcare to participate and perceived or experienced social stigma creating fear of the involvement of child protective services if AUD is disclosed.12 Further, no AUD pharmacotherapy has been shown to be safe for women who are pregnant or breastfeeding, limiting treatment options during this time. Similarly, for youths, no pharmacotherapies are FDA-approved to treat AUD in those ≤18 years of age, and no trials of AUD treatment among youths with ALD have been conducted. Despite the knowledge that most adults with AUD began using alcohol during the teenage years, the majority of efforts developed to treat AUD have not focused on identification and intervention during adolescence, which may be a key time for behavioral change. Further, the delivery of AUD behavioral therapy for youths is best if the family and caregivers partake, which again will be dependent on the ability of not only the individuals but also their social circle to participate. POTENTIAL SOLUTIONS Several provider, hospital, research, and societal solutions to address barriers in AUD management in ALD are outlined in Figure 3. On an individual GI/Hepatology provider level, the universal implementation of standardized screening tools for AUD to all patients with ALD at the time of the first clinical encounter should be straightforward to implement. In addition to this, the delivery of an AUD pharmacotherapy curriculum to GI/Hepatology trainees, nurses, and clinicians could empower them with the knowledge and skills to initiate AUD pharmacotherapy among their ALD patients. This would be especially important in settings where access to addiction medicine is limited. From a hospital level, providing language and transportation services to facilitate access to AUD behavioral therapy would be specifically helpful to engage vulnerable populations. Further, universal and quick access to inpatient and outpatient addiction medicine consultative services, social work, and psychiatry are essential. From an academic level, the development of studies, which evaluate AUD treatment and outcomes among those with advanced ALD, are needed in addition to the inclusion of previously understudied and vulnerable populations as outlined above. From a society level, it is vital to address the stigma attached to a diagnosis of AUD to empower patients to seek appropriate help without worry about judgment or discrimination. This could involve public education campaigns that emphasize AUD as a disease as opposed to a personal choice and highlight how appropriate treatment of AUD can lead to disease remission and improve other alcohol-associated harms including ALD.FIGURE 3: Potential solutions to address disparities in AUD treatment among those with ALD. Abbreviations: ALD, alcohol-associated liver disease; AUD, alcohol use disorder.CONCLUSIONS AND FUTURE CONSIDERATIONS AUD is a preventable cause of liver-related morbidity and mortality, and AUD treatment is associated with improved outcomes, especially among those with ALD. Yet the use of AUD treatment in those with ALD is discouragingly low due to the paucity of well-executed clinical trials and patient and provider barriers, with additional unique barriers faced by underrepresented and vulnerable members of society. As hepatology providers caring for these patients, our discipline needs to begin gathering AUD treatment tools to put in our toolbox. Importantly, these tools will need to incorporate considerations surrounding stigma, culture, diversity, and equity in order to provide the best care for our diverse patient population.

Heavy-Drinking Smokers: Pathophysiology and Pharmacologic Treatment Options

Issue Highlights

The fungal microbiota plays an important role in the pathogenesis of alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). In this study, we aimed to compare changes of the fecal fungal microbiota between patients with ALD and NAFLD and to elucidate patterns in different disease stages between the two conditions. We analyzed fungal internal transcribed spacer 2 (ITS2) sequencing using fecal samples from a cohort of 48 patients with ALD, 78 patients with NAFLD, and 34 controls. The fungal microbiota differed significantly between ALD and NAFLD. The genera Saccharomyces, Kluyveromyces, Scopulariopsis, and the species Candida albicans (C. albicans), Malassezia restricta (M. restricta), Scopulariopsis cordiae (S. cordiae) were significantly increased in patients with ALD, whereas the genera Kazachstania and Mucor were significantly increased in the NAFLD cohort. We identified the fungal signature consisting of Scopulariopsis, Kluyveromyces, M. restricta, and Mucor to have the highest discriminative ability to detect ALD vs NAFLD with an area under the curve (AUC) of 0.93. When stratifying the ALD and NAFLD cohorts by fibrosis severity, the fungal signature with the highest AUC of 0.92 to distinguish ALD F0-F1 vs NAFLD F0-F1 comprised Scopulariopsis, Kluyveromyces, Mucor, M. restricta, and Kazachstania. For more advanced fibrosis stages (F2-F4), the fungal signature composed of Scopulariopsis, Kluyveromyces, Mucor, and M. restricta achieved the highest AUC of 0.99 to differentiate ALD from NAFLD. This is the first study to identify a fungal signature to differentiate two metabolic fatty liver diseases from each other, specifically ALD from NAFLD. This might have clinical utility in unclear cases and might hence help shape treatment approaches. However, larger studies are required to validate this fungal signature in other populations of ALD and NAFLD.

Changing Epidemiology of Cirrhosis and Hepatic Encephalopathy

The American Psychiatric Association Practice Guideline for the Pharmacological Treatment of Patients With Alcohol Use Disorder.

Although epidemiological studies indicate increased fracture risk in women with alcohol-associated liver disease (AALD) and metabolic-associated fatty liver disease (MAFLD), data about their micro-scale bone features are still limited. We aimed to characterize bone quality changes in the anterior mid-transverse part of the first lumbar vertebral body collected from 32 adult postmenopausal females. Based on pathohistological assessment of the liver tissue, individuals were divided into AALD (n = 13), MAFLD (n = 9), and control group (n = 10). We analyzed trabecular and cortical micro-architecture (using micro-computed tomography), bone mechanical properties (using Vickers microhardness tester), osteocyte lacunar network and bone marrow adiposity morphology (using optic microscopy). Data were adjusted to elude the covariant effects of advanced age and body mass index on our results. Our data indicated a minor trend toward deteriorated bone quality in MAFLD women, presented in impaired trabecular and cortical micro-architectural integrity, which could be associated with bone marrow adiposity alterations noted in these women. Additionally, we observed a significant decline in micro-architectural, mechanical, and osteocyte lacunar features in lumbar vertebrae collected from the AALD group. Lastly, our data indicated that vertebral bone deterioration was more prominent in the AALD group than in the MAFLD group. Our data suggested that MAFLD and AALD are factors that could play a part in compromised vertebral strength of postmenopausal women. Also, our data contribute to understanding the multifactorial nature of bone fragility in these patients and highlight the necessity for developing more effective patient-specific diagnostic, preventive, and therapeutic strategies.

New Challenges in Addiction Medicine: COVID-19 Infection in Patients With Alcohol and Substance Use Disorders-The Perfect Storm.

Alcohol-associated liver disease (ALD) is one of the most devastating complications of alcohol use disorder (AUD), an increasingly prevalent condition. Medical addiction therapy for AUD may play a role in protecting against the development and progression of ALD. To ascertain whether medical addiction therapy was associated with an altered risk of developing ALD in patients with AUD. This retrospective cohort study used the Mass General Brigham Biobank, an ongoing research initiative that had recruited 127 480 patients between its start in 2010 and August 17, 2021, when data for the present study were retrieved. The mean follow-up duration from AUD diagnosis was 9.2 years. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis codes were used to identify ALD and AUD diagnoses. Medical addiction therapy was defined as the documented use of disulfiram, acamprosate, naltrexone, gabapentin, topiramate, or baclofen. Patients were considered to be treated if they initiated medical addiction therapy before the relevant outcome. Adjusted odds ratios (aORs) for the development of ALD and hepatic decompensation were calculated and adjusted for multiple risk factors. The cohort comprised 9635 patients with AUD, of whom 5821 were male individuals (60.4%), and the mean (SD) age was 54.8 (16.5) years. A total of 1135 patients (11.8%) had ALD and 3906 patients (40.5%) were treated with medical addiction therapy. In multivariable analyses, medical addiction therapy for AUD was associated with decreased incidence of ALD (aOR, 0.37; 95% CI, 0.31-0.43; P < .001). This association was evident for naltrexone (aOR, 0.67; 95% CI, 0.46-0.95; P = .03), gabapentin (aOR, 0.36; 95% CI, 0.30-0.43; P < .001), topiramate (aOR, 0.47; 95% CI, 0.32-0.66; P < .001), and baclofen (aOR, 0.57; 95% CI, 0.36-0.88; P = .01). In addition, pharmacotherapy for AUD was associated with lower incidence of hepatic decompensation in patients with cirrhosis (aOR, 0.35; 95% CI, 0.23-0.53, P < .001), including naltrexone (aOR, 0.27; 95% CI, 0.10-0.64; P = .005) and gabapentin (aOR, 0.36; 95% CI, 0.23-0.56; P < .001). This association persisted even when medical addiction therapy was initiated only after the diagnosis of cirrhosis (aOR, 0.41; 95% CI, 0.23-0.71; P = .002). Results of this study showed that receipt of medical addiction therapy for AUD was associated with reduced incidence and progression of ALD. The associations of individual pharmacotherapy with the outcomes of ALD and hepatic decompensation varied widely.

Closing the Care Gap: Management of Alcohol Use Disorder in Patients with Alcohol-associated Liver Disease

Alcohol-associated liver disease (ALD) is a leading cause of liver-related deaths in the United States and worldwide, occurring in persons with alcohol use disorder (AUD). Effective treatment of AUD is essential to curtail the progression of ALD and/or reverse the disease course, yet there is a paucity of information on care models for the concomitant treatment of AUD in persons with ALD, particularly when liver transplant is not imminent or warranted. Here, we reviewed existing literature on care models for the concomitant treatment of ALD and AUD among individuals not undergoing liver transplant evaluation or consideration. A comprehensive search of electronic databases including Cochrane Library, CINAHL, Ovid MEDLINE, Ovid Embase, Scopus, Google Scholar, PubMed, and Web of Science Core Collection from inception to July 2024 was conducted to identify original studies reporting care for both ALD and AUD in persons not undergoing liver transplant evaluation or consideration. From the 1146 publications identified, 43 studies were selected for further review, of which three articles were selected for data charting and inclusion in the review. Concomitant treatment of ALD and AUD were implemented both within inpatient and outpatient settings, with multidisciplinary care teams typically involving hepatology and addiction medicine and/or addiction psychiatry. One study showed that attention and care for AUD led to improvement in liver disease and a decrease in emergency department visits and frequency of hospitalization. The studies reviewed suggest that concomitant care for ALD and AUD in the nontransplant setting may improve outcomes for some patients. The limited number of studies highlights the need for more prospective and longitudinal studies evaluating concomitant treatment, especially in persons for whom liver transplant may not be an option or a consideration.

Pharmacotherapy for Alcohol Use Disorder Is Underutilized Among Commercially Insured Adults With Alcohol-Associated Liver Disease

This study investigates the differential impact of fecal fungal microbiota on the pathogenesis of alcohol-associated liver disease (ALD) and metabolic-associated fatty liver disease (MAFLD). We aim to delineate distinct microbial patterns across various stages of each disease. We conducted fungal internal transcribed spacer 2 (ITS2) sequencing analysis on fecal samples from 48 ALD patients, 55 MAFLD patients, and 64 healthy controls (HCs). Distinct fungal microbiota profiles were significantly identified between the ALD and MAFLD patients. In the ALD group, genera such as Trichosporon, Davidiella and Asterotremella along with species like Trichosporon unclassified and Davidiella unclassified were elevated compared to those in the MAFLD group. Conversely, Fungi unclassified, Rhizopus, Periconia, and Candida albicans were more prevalent in MAFLD patients. A specific fungal signature comprising Asterotremella_pseudolonga, Malassezia_restricta and Malassezia, was notably effective in differentiating ALD from MAFLD, achieving an area under the curve (AUC) of 0.94. Periconia and Periconia byssoides were more abundant in non-obese MAFLD patients compared to obese MAFLD and HCs. Rhizopus microsporus var. chinensis and var. rhizopodiformis, along with Pleosporales unclassified, were predominantly found in MAFLD patients with moderate to severe hepatic steatosis (HS). The genera Pleosporales_unclassified and the species Candida_albicans were markedly elevated in ALC patients when contrasted with AFL or HCs. This investigation introduces a novel fungal signature that successfully differentiates between ALD and MAFLD, underscoring Pleosporales unclassified, as biomarkers for disease progression in ALD and MAFLD. The findings also suggest a significant role for Periconia in the progression of non-obese MAFLD.

Comment on: Impact of the COVID-19 pandemic on liver disease-related mortality rates in the United States

Screening for Alcohol Misuse and Alcohol-Related Behaviors Among Combat Veterans